The replication-defective avian erythroblastosis virus, E26, induces a mixed erythroid/myeloid leukemia in chickens. E26 includes elements from two proto-oncogenes, chicken proto-myb and chicken proto-ets, and delta gag from the viral gag gene. Human genomic clones homologous to the ets region were cloned and shown to be related to the v-ets region by partial sequence analysis. The human ets-1 locus on chromosome 11 encodes a single mRNA of 6.8 kb; the human ets-2 locus encodes three mRNAs of 4.7 kb, 3.2 kb and 2.7 kb. The Hu-ets-1 and Hu-ets-2 genes have recently been shown to be transposed in certain leukemias. Because of the significance of ets in neoplasia, we embarked on a search for other human genes closely related to ets. A cDNA library was prepared from a human COLO 320 cell line which expresses very high levels of ets-specific transcripts. Two cDNA clones reactive with the Hu-ets-2 probe were isolated. Characterization of these clones by restriction mapping and sequence analysis revealed that they represented the complete coding sequence of a novel human gene named erg (ets-related gene). The erg gene shows a homology of approximately 40% and approximately 70% to two domains of the 5' and 3' regions of the v-ets oncogene. One of the cDNAs (erg-2) differs from erg-1 by a splicing event that causes a coding frameshift near the NH-2 terminus, resulting in an additional 99 a-a insertion at the amino terminal end. There is preliminary evidence to state that erg-2 may use a different translation initiation and poly-adenylation signal. The full-length cDNA clones, erg-1 and erg-2, are being expressed in vitro and in vivo in E. coli and in mammalian cells. The erg gene has been localized on human chromosome 21. In situ hybridization studies for chromosomal localization of the erg gene are in progress. Thus, the precise location of the erg gene and analysis of the erg locus in different human cancers, Down's syndrome and Alzheimer's disease should make it possible to determine if amplification, translocation or rearrangement of this gene can be linked to any of these diseases.